What Does the Evidence Say About Immunotherapy Rechallenge in RCC?

Treatment of metastatic renal cell carcinoma (RCC) continues to rapidly evolve, with various combinations of immune checkpoint inhibitors (ICIs) and targeted tyrosine kinase inhibitors improving outcomes in the first-line setting. However, a significant subset of patients fail to respond to these therapies, and many patients eventually progress, necessitating effective therapeutic options in the treatment-refractory setting.

Several abstracts presented at the American Society of Clinical Oncology (ASCO) annual meeting addressed this concern, and in this exclusive MedPage Today video, Kathryn Beckermann, MD, PhD, an assistant professor of medicine at Vanderbilt University Medical Center in Nashville, Tennessee, discusses some of the studies that address treatment in the refractory setting.

Following is a transcript of her remarks:

We had some important trials that answered questions that were on many of our minds. Over the last 5 years we’ve had an advancement in the frontline treatment for patients with metastatic RCC. And one of the big trials presented today asked the question, should we be continuing immunotherapy in the refractory space? Patients at this time in the community, and we’ve looked at this, are getting that without the data to support it.

So CONTACT-03 reported out at ASCO this year asked that very specific question. If a patient had progressed on first-line therapy, could we achieve better cures? Could we achieve more durable response in the second-line setting? And they did this by randomizing patients who’d progressed on prior immune therapy to either cabozantinib [Cabometyx] monotherapy or cabozantinib with the PD-L1 agent atezolizumab [Tecentriq].

The trial was flatly negative; there was no benefit. And additionally, there was seemingly some increased toxicity. Maybe not a surprise if you put two medicines together, more [toxicity]. And so, I think, this should strongly encourage the physicians not to be continuing ICI without data.

There’s some additional studies going forward that I think will either help inform this overall question. So there’s another trial called NIVO-2, it’s just finished enrollment and is asking a similar question post-first-line therapy, should we continue ICI there? The partners are different. So it’s looking at a PD-1 agent with nivolumab [Opdivo] in combination with tivozanib [Fotivda]. So I think that’s either going to really solidify that answer for us as a community or maybe call into question if it’s a specific agent or something like that.

I think in the refractory setting, the things I see coming up in the near future, we’ve had a lot of early-phase data presented on HIF [hypoxia-inducible factor] blockade. A trial in progress was presented here on a novel HIF agent. And actually just last month, an HIF combination with cabozantinib was presented. At this ASCO 2023, there was a belzutifan [Welireg] plus lenvatinib [Lenvima] combination, 30 patients treated, an objective response rate that was certainly reasonable in a refractory patient population of about 50%. Again, early, early-phase data, but I think there’s a lot of excitement around that novel target.

So there’s a randomized phase III trial that has closed and it was in refractory patients, third- and fourth- line setting. They either got HIF inhibition with belzutifan or they were randomized to mTOR [mammalian target of rapamycin] inhibition with everolimus [Afinitor]. So I think that that will maybe be the next new target that we’re all looking forward to seeing the data.

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